Blood, 15 August 2002, Vol. 100, No. 4, pp. 1111-1112
Platelet formation: a link between apoptosis and
differentiation
Proteases of the caspase family represent the central
executioners of the apoptotic process. Many recent observations suggest that caspases, beyond their well known main role in cell death, exert
important functions in other cellular processes, including cell
differentiation and control of T-cell proliferation and cell-cycle progression. Concerning the role of caspases in cell differentiation, recent studies suggest that caspase activation is required for normal
keratinocyte differentiation (Weil et al, Current Biol. 1999;9:361-364), for lens fiber differentiation (Ishizaki et al, J
Cell Biol. 1998;140:153-158), and for erythroid maturation (Zermati et
al, J Exp Med. 2001;193:247-254).
De Botton and colleagues (page 1310) elegantly demonstrate that caspase
activation within megakaryocytes is required for platelet production.
They present evidence that in vitro-grown megakaryocytes exhibit
during their terminal stages of maturation the activation of caspases 3 and 9. Two lines of evidence suggest that this spontaneous caspase
activation observed under physiologic conditions is required for
platelet production: (1) caspase inhibitors markedly decrease proplatelet formation, and (2) megakaryocytic cells overexpressing the
antiapoptotic protein Bcl-2 exhibited reduced proplatelet formation.
The most interesting and intriguing finding of this study, however,
consisted in the observation that maturing megakaryocytes, before
propletelet formation, exhibit a punctuate cytoplasmic distribution of
caspase 3, suggesting a localized caspase activation. In contrast,
senescent megakaryocytes exhibited a diffuse cytosolic localization.
According to these findings, it was proposed that during late
megakaryocytic maturation a compartmentalized caspase 3 activation may
contribute to proplatelet formation, while at terminal stages of
megakaryocytic maturation, in senescent megakaryocytes, caspase
activation switches from a localized to a diffuse cytosolic activation
with consequent induction of apoptosis.
The role of the localized caspase activation observed during
proplatelet formation remains to be defined, at the moment. In this
context, it seems reasonable to assume that this localized caspase 3 may contribute to the changes in myosin function and actin
cytoskeleton tightly involved in the mechanism of proplatelet formation. The elucidation of the molecular mechanisms responsible for
this differential and sequential caspase activation occurring during
megakaryocytic maturation will provide a major contribution to the
understanding of the mechanisms linking differentiation and apoptosis.
Ugo Testa
Istituto Superiore di Sanita, Rome
